A double-layer soluble microneedle patch for local fat reduction and its preparation method and application

Abstract

The present invention relates to a double-layer soluble microneedle patch for local fat reduction, and a preparation method and application thereof, wherein the microneedles are loaded with anti-inflammatory and fat-reducing drugs. The present invention simultaneously loads the fat-reducing drug and nanoparticles capable of sustained-release anti-inflammatory drugs into the same microneedle, and relieves the adverse reactions of the drugs while administering the drugs. The sustained-release anti-inflammatory drug dosage form is loaded into the microneedles, so that the fat-reducing drug is first released in large quantities, destroying fat cells and causing an inflammatory reaction, and the anti-inflammatory drug is then slowly released at the location where the inflammation occurs, so that the concentration of the anti-inflammatory drug is maintained at the treatment threshold, thereby achieving a more optimized balance between the treatment effect and the side effects, and increasing the efficacy and patient compliance.

Description

Technical Field

[0001] The present invention relates to the field of transdermal drug delivery of microneedle patches, and in particular to a double-layer soluble microneedle patch for local fat reduction, and a preparation method and application thereof. Background Art

[0002] Currently, the most commonly used surgical methods for reducing subcutaneous fat tissue include liposuction and abdominoplasty. However, these surgical methods increase the risk of serious adverse reactions, and some patients are reluctant to undergo liposuction due to pain during surgery. Therefore, non-surgical methods may be suitable for reducing fat tissue, especially localized fat reduction. The destruction of fat cells is an irreversible physical process and is often used to reduce localized fat tissue.

[0003] At present, subcutaneous injection is usually used for application. During one treatment, 20-30 injections are required. At the same time, the injection site will be red and swollen for several weeks because fat cells are destroyed. Even the facial nerves may be damaged due to improper subcutaneous injection operation. It is difficult to achieve the expected effect in one time, so patients need to go to the hospital for injection several times, which greatly reduces the compliance of patients. Microneedle technology is a new drug delivery method. Through the soluble microneedle array, the skin is penetrated to open the channel of the skin. The fat-reducing drug is dissolved by the interstitial fluid and directly enters the human body from the channel to play a role. Its targeting and high drug delivery efficiency are very consistent with the requirements of local precise fat reduction. However, the disadvantages of local fat reduction still exist. After taking the drug, redness and swelling will occur at the injection site for several weeks. Usually, anti-inflammatory drugs are used to eliminate the redness and swelling. Oral, injection, application and other drug delivery methods can be used to use anti-inflammatory drugs. If these methods are selected, the inflammatory reaction can only be known after the weight loss microneedle patch is removed or the user feels obvious discomfort. At this time, the inflammatory reaction usually has existed for a certain period of time, so there is a situation of untimely medication, and it may cause some special people to have more serious conditions. In addition, if you choose to eliminate redness and swelling by oral or injection, because it is not directly given to the local area, there is a long response period after medication and there are side effects because the drug acts on the whole body; if fat-reducing drugs and anti-inflammatory drugs are used at the same time, because the dissolution of fat cells and the subsequent inflammatory response have a time sequence, mixing the two chemical drugs and using them at the same time will be insufficient for the purpose of exerting the efficacy of the drugs and reducing side effects. Summary of the invention

[0004] In view of the obvious adverse reactions after subcutaneous injection in local fat reduction, the low patient compliance caused by multiple subcutaneous injections, and the uncertainty caused by mixed use of drugs, the present invention provides a double-layer microneedle patch for local fat reduction and its preparation method and application. The microneedle patch can penetrate the skin to administer drugs, so that the user can maintain a good appearance, and at the same time, the pharmacokinetic properties of the two drugs can be distinguished and optimized, thereby enhancing the fat reduction effect, reducing inflammatory reactions, and thus alleviating the redness and swelling of the drug administration site.

[0005] One inventive point of the present invention is to provide a double-layer soluble microneedle patch for local fat reduction, wherein the microneedles include anti-inflammatory drugs and fat-reducing drugs.

[0006] Furthermore, the mass ratio of the anti-inflammatory drug to the fat-reducing drug is 1:(80-200).

[0007] Furthermore, the fat-reducing drug is selected from at least one of a fat dissolving agent, a fat decomposing agent, and a fat metabolism promoting agent.

[0008] Furthermore, the needle body of the microneedle is divided into a first layer and a second layer from the outside to the inside, the first layer includes an anti-inflammatory drug and a first carrier loaded with the anti-inflammatory drug, and the second layer includes a fat-reducing drug and a second carrier loaded with the fat-reducing drug;

[0009] Preferably, the first carrier and the second carrier are swellable materials;

[0010] More preferably, the swellable material is polyethylene glycol diacrylate (PEGDA) and / or poly(lactic-co-glycolic acid) (PLGA).

[0011] Furthermore, the first layer further comprises a soluble matrix, preferably a polysaccharide polymer matrix, and more preferably hyaluronic acid.

[0012] Furthermore, the needle body is conical in shape, with a length of 650 to 850 μm, a diameter of the bottom of the needle body of 300 to 400 μm, and a tip diameter of less than 10 μm.

[0013] Another inventive point of the present invention is to provide a method for preparing a double-layer soluble microneedle patch for local fat reduction.

[0014] The anti-inflammatory drug and the fat-reducing drug are added into the microneedle mold containing holes in sequence according to the mass ratio of 1:(80-200); the steps are:

[0015] 1) Adding fat-reducing drugs into the mold and solidifying them to obtain microneedle 1;

[0016] 2) Add the anti-inflammatory drug into the mold, and after drying, use a volatile solvent to wet the needle body, insert the microneedle back into the mold and dry it, and after demolding, obtain a double-layer soluble microneedle.

[0017] Furthermore, the preparation method is:

[0018] 1) The fat-reducing drug and the second carrier are fully stirred at a mass ratio of 1:(8-15) to obtain a mold liquid 1, and the mold liquid 1 is added to a microneedle mold containing holes, so that the mold liquid fills the microholes and then solidifies to obtain a microneedle 1;

[0019] 2) The anti-inflammatory drug and the first carrier are prepared into nanoparticles in a mass ratio of 1:(1-5), added into a microneedle mold containing holes, and after drying, the needle body is moistened with a volatile solvent, the microneedle is inserted back into the mold and dried, and a double-layer microneedle is obtained after demolding.

[0020] Furthermore, the preparation method, the step 2) also includes fully stirring the nanoparticles and the soluble matrix at a mass ratio of 1: (20 to 80) to obtain a second mold liquid, adding the second mold liquid to a microneedle mold containing holes, drying and removing the remaining mold liquid second, wetting the needle body with a volatile solvent, inserting the microneedle one back into the mold and drying it, and obtaining a double-layer microneedle after demolding.

[0021] The third invention of the present invention is to provide an application of the above-mentioned double-layer soluble microneedle patch in the preparation of a weight-loss drug for treating and eliminating redness and swelling.

[0022] Compared with the prior art, the advantages of the present invention are:

[0023] (1) The present invention simultaneously loads nanoparticles of fat-reducing drugs and sustained-release anti-inflammatory drugs into the same microneedle, which facilitates drug administration while alleviating adverse drug reactions. The sustained-release anti-inflammatory drugs are loaded into the microneedles to achieve a large-scale release of the fat-reducing drugs first, destroying the pro-inflammatory fat cells, and then slowly releasing the anti-inflammatory drugs at the site of inflammation, so that the concentration of the anti-inflammatory drugs is maintained at an appropriate treatment threshold, thereby achieving a more optimized balance between the treatment effect and the side effects, thereby increasing the efficacy and patient compliance.

[0024] (2) The microneedle patch of the present invention can achieve the therapeutic effect through a single administration while alleviating the unavoidable adverse reactions of the treatment and reducing the impact of the medication on the user's appearance.

[0025] (3) The microneedle patch of the present invention allows the drug-loaded microneedles to penetrate the skin by finger pressure or mechanical tapping, and one administration replaces 20-30 subcutaneous injections, which is convenient for administration and reduces the pain of the user. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 exemplifies the particle size distribution of dexamethasone nanoparticles of the present invention.

[0027] Figure 2is a stereomicroscope image of an exemplary double-layer microneedle array demonstration of the present invention.

[0028] Figure 3 is a stereomicroscope image of an exemplary microneedle array of the present invention.

[0029] Figure 4 It is a mechanical force-displacement curve showing the exemplary double-layer microneedle patch of the present invention, which shows the ability of the microneedles to penetrate the skin. The mechanical force of the microneedles reaches 0.05N / needle, which can effectively penetrate the skin of experimental animals.

[0030] Figure 5 are data showing the uniformity of loading of exemplary microneedle patches of the present invention.

[0031] Figure 6 is a graph showing the cumulative transdermal release of sodium deoxycholate in phosphate buffered saline from the microneedle patch of the present invention over time (0 to 24 hours).

[0032] Fig. 7A It shows the drug administration and sampling methods using a blank microneedle array and a dexamethasone / sodium deoxycholate double-layer microneedle.

[0033] Figure 7B The figure shows the H&E staining of mouse skin on both sides of the body after treatment with dexamethasone / sodium deoxycholate double-layer microneedles.

[0034] Specific implementation method

[0035] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below. However, it should be understood that the description here is only used to explain the present application and is not used to limit the scope of the present application.

[0036] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0037] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0038] Example 1

[0039] This embodiment provides a double-layer soluble microneedle patch for local fat reduction, in which anti-inflammatory drugs and fat-reducing drugs are loaded.

[0040] As a further preferred embodiment, the mass ratio of the anti-inflammatory drug to the fat-reducing drug is 1:(80-200).

[0041] As a further preferred embodiment, the fat-reducing drug is selected from at least one of a fat dissolving agent, a fat decomposing agent, and a fat metabolism promoting agent. The type of the anti-inflammatory drug is not specifically limited in the present invention. Strictly speaking, as long as it can achieve an anti-inflammatory effect, it can be a candidate variety.

[0042] As a further preferred embodiment, the needle body of the microneedle has a first layer and a second layer from the outside, the first layer includes an anti-inflammatory drug and a first carrier loaded with the anti-inflammatory drug, and the second layer includes a fat-reducing drug and a second carrier loaded with the fat-reducing drug;

[0043] Preferably, the first carrier and the second carrier are swellable materials;

[0044] More preferably, the swellable material is polyethylene glycol diacrylate (PEGDA) and / or poly(lactic-co-glycolic acid) (PLGA).

[0045] The first layer is loaded with sustained-release anti-inflammatory drugs, and the second layer is loaded with fat-reducing drugs, so that fat-dissolving agents, fat decomposing agents, or fat metabolism promoters can be released immediately after administration, leaving the sustained-release anti-inflammatory drugs to relieve inflammation caused by fat destruction. One microneedle administration replaces multiple subcutaneous injections and relieves inflammatory reactions at the same time, reducing the pain of the user and maintaining a good image of the user.

[0046] As a further preferred embodiment, the first layer further comprises a soluble matrix, preferably a polysaccharide polymer matrix, and more preferably hyaluronic acid.

[0047] The disadvantage of existing dosage forms of fat-reducing drugs for local fat reduction is that multiple subcutaneous injections and multiple treatments are required for one-time administration; secondly, redness and swelling will occur at the injection site for several weeks after medication, resulting in poor efficacy and poor treatment compliance for patients. Therefore, in combination with the above problems, the present invention selects a swelling material as the main carrier of the fat-reducing drug, which can release the drug therein in the body, and the present invention preferably uses polyethylene glycol diacrylate (PEGDA); in order to allow users to maintain a good appearance, the present invention selects a fast-dissolving polymer material hyaluronic acid as the first layer of the microneedle needle body, and loads the sustained-release polylactic acid-glycolic acid copolymer (PLGA) and anti-inflammatory drugs to prepare nanoparticles, in the body, as the hyaluronic acid layer quickly dissolves, the sustained-release anti-inflammatory drug nanoparticles remain in the body and are slowly released, while exposing the second layer of the needle body layer containing the fat-reducing drug to release the drug, with the release of the fat-reducing drug, the fat cells are destroyed, and an inflammatory reaction occurs. At this time, the sustained-release anti-inflammatory drug nanoparticles retained in the body continuously release the anti-inflammatory drug, reduce the inflammatory reaction, and thus alleviate the redness and swelling of the administration site.

[0048] In actual operation, the rate at which anti-inflammatory drug nanoparticles remain in the body and are slowly released is related to the particle size of the nanoparticles. The slow release rate is used to determine whether the anti-inflammatory drug takes effect within an appropriate period of time to ensure the drug's medicinal properties and effectiveness.

[0049] As a further preferred embodiment, the needle body is conical, with a length of 650-850 μm, preferably 850 μm, a bottom diameter of 300-400 μm, preferably 350 μm, and a tip diameter of less than 10 μm.

[0050] The tip of the microneedle body refers to the top of the microneedle body, and has a diameter of 0 to 10 μm.

[0051] In order to avoid pain caused by touching the nerves and ensure drug delivery efficiency and efficacy, it is necessary to reasonably design the microneedle shape, length, array distribution, etc. Preferably, the microneedle mold is made of polydimethylsiloxane (PDMS) material to ensure that the prepared microneedles can be completely demolded and have sufficient mechanical properties. The mold base is a circular PDMS material with a diameter of 22mm. The base has a 2mm high circle to prevent the loss of drug solution during the preparation of microneedles, saving costs. The three-dimensional size of the microneedle array and the number of microneedles used can be adjusted according to the administration site and the required dose to achieve the purpose of optimal drug delivery.

[0052] As a further preferred embodiment, it comprises microneedles, a microneedle substrate and an adhesive tape.

[0053] The microneedles and their substrate are supported by a breathable, hypoallergenic soft medical tape, allowing the microneedles to be applied to the skin surface.

[0054] As a further preferred embodiment, the microneedles form a microneedle array. Preferably, the microneedle array adopts a 10×10 square array, and the distance between adjacent microneedle tips is 600 μm.

[0055] Microneedle array local drug delivery can adjust the shape and length of the microneedles according to the location and area of ​​fat reduction. A single use of the microneedle product can replace dozens of injections, and the needle length can be adjusted to adapt to the skin thickness of each fat reduction area to avoid nerve damage.

[0056] The swellable material in the microneedle array serves as a drug carrier and also as a substrate support, acting as a drug reservoir, promoting the short-time release of the drug to the target dose and reducing the usage time of the microneedle patch.

[0057] Example 2

[0058] According to the content of this application, the double-layer microneedle patch described in Example 1 was prepared, and the specific description is as follows:

[0059] This embodiment provides a method for preparing a double-layer soluble microneedle patch for local fat reduction.

[0060] The anti-inflammatory drug and the fat-reducing drug are added into the microneedle mold containing holes in sequence according to the mass ratio of 1:(80-200); the steps are:

[0061] 1) Adding fat-reducing drugs into the mold and solidifying them to obtain microneedle 1;

[0062] 2) Add the anti-inflammatory drug into the mold, and after drying, use a volatile solvent to wet the needle body, insert the microneedle back into the mold and dry it, and after demolding, obtain a double-layer soluble microneedle.

[0063] As a further preferred embodiment, the preparation method is:

[0064] 1) The fat-reducing drug and the second carrier are fully stirred at a mass ratio of 1:(8-15) to obtain a mold liquid 1, and the mold liquid 1 is added to a microneedle mold containing holes, and vacuumed for 20-30 minutes at a pressure of -0.1 to -0.06 MPa, centrifuged at room temperature of 23-27° C., and centrifuged at 3000-4000 rpm for 15-25 minutes to allow the mold liquid to fill the micropores and then solidify to obtain microneedle 1;

[0065] 2) The anti-inflammatory drug and the first carrier are prepared into nanoparticles at a mass ratio of 1: (1-5), and the nanoparticles and the soluble matrix are fully stirred at a mass ratio of 1: (20-80) to obtain a second mold liquid, and the second mold liquid is added to the microneedle mold containing holes, and vacuumed at -0.1 to -0.06 MPa pressure for 20-30 minutes, at room temperature of 23-17°C, centrifuged at 3000-4000 rpm, and centrifuged for 15-25 minutes, and the excess drug-containing mold liquid on the mold surface is removed and recovered, and the drying temperature is 30-40°C to remove the remaining matrix. A small amount of volatile solvent is used to wet the needle body, and the microneedle 1 is inserted back into the mold and dried, and a double-layer microneedle is obtained after demolding.

[0066] 3) The obtained microneedles and their substrates are applied to adhesive tape and packaged for later use.

[0067] Example 3

[0068] According to the content of this application, the double-layer microneedle patch of Example 1 prepared in Example 2 is specifically described as follows:

[0069] This embodiment also provides the use of the double-layer microneedle patch described in Example 1 in the preparation of a weight loss drug for treating and eliminating redness and swelling.

[0070] Preferably, the method for using the double-layer microneedle patch is to stick the double-layer microneedle patch loaded with anti-inflammatory drugs and fat-reducing drugs on the skin, press the microneedle array into the skin by finger pressing or mechanical tapping, and remove it after releasing the drugs.

[0071] Example 4

[0072] According to the content of this application, the double-layer microneedle patch of this application is specifically described. If the specific experimental steps or conditions are not specified in the embodiments, the conventional experimental steps or conditions described in the literature in this field can be used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional reagent products that can be purchased commercially.

[0073] The present invention is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed by the present invention.

[0074] At least some of the reagents and materials involved in the embodiments, comparative examples and test examples of the present invention are from the following sources:

[0075] The experimental animals were SPF-grade female C57BL / 6J mice purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.;

[0076] Sodium deoxycholate (high-grade pure) was purchased from Aladdin Biochemical Technology Co., Ltd.;

[0077] Dexamethasone (98%) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0078] Medical grade HA-EP120-40 low-molecular-weight sodium hyaluronate was purchased from Huaxi Freda Biopharmaceutical Co., Ltd.

[0079] Poly(lactic-co-glycolic acid) (PLGA) was purchased from MedChemExpress;

[0080] Polyethylene glycol diacrylate (PEGDA) was purchased from Aladdin Biochemical Technology Co., Ltd.

[0081] The fat-reducing effect was demonstrated by an animal experiment on mice. GraphPad Prism was used for statistical analysis, including t-test and Two-way ANOVA, and the experimental parallel data were obtained from at least 3 different individuals. * represents p value less than or equal to 0.05, ** represents p value less than or equal to 0.01, and *** represents p value less than or equal to 0.001.

[0082] This test example is described by taking dexamethasone as an example, and is not intended to be limiting.

[0083] Experimental Example 1: Preparation of drug-loaded microneedles 1

[0084] 1. Preparation of Dexamethasone / PLGA Nanoparticles

[0085] 2 mg dexamethasone and 6 mg PLGA were dissolved in 1 mL acetone and added to an aqueous phase (2 mL) containing 0.5% (w / v) HS-15. The HS-15 was stirred at 300 rpm and room temperature (25°C ± 2°C) for 24 h to evaporate the organic solvent. After freeze drying, dexamethasone PLGA nanoparticle powder was obtained. Figure 1 .

[0086] 2. Preparation of Dexamethasone and Sodium Deoxycholate Microneedle Patches

[0087] Add 300 mg of sodium deoxycholate and 15 μL of 2-hydroxy-2-methylpropiophenone to 3 g of PEGDA, stir at 300 rpm and room temperature 25°C ± 2°C for 2 h in a dark environment, and mix thoroughly to obtain mold liquid 1. Take 200 μL of mold liquid 1 and add it to the cleaned and dried mold, evacuate at -0.1 MPa pressure for 30 min, centrifuge at 25°C, 3500 rpm for 20 min, and UV cure for 2 min. Then add 300 μL of mold liquid, centrifuge at 25°C, 3500 rpm for 10 min, and UV cure for 2 min. Microneedle array 1 is obtained.

[0088] Add a magnetic stirrer to the double distilled water and stir at 1000 rpm, and evacuate at -0.1 MPa pressure for 30 minutes. Weigh 120 mg HA and 3 mg of prepared dexamethasone PLGA nanoparticle powder and add them to 3 mL of double distilled water, stir at 300 rpm at room temperature for 7 hours to prepare mold liquid 2. Take 50 μL of mold liquid 2 and add it to the mold, evacuate at -0.1 MPa pressure for 30 minutes, centrifuge at 25°C, 3500 rpm, 15 minutes, and dry at 35°C for 2 hours. Add 150 μL of double distilled water, centrifuge at 25°C, 3500 rpm, 5 minutes, wet the surface of the needle body, reinsert the prepared microneedle array 1 into the mold, and dry at 35°C for 8 hours. The obtained microneedle patch is applied to medical tape and packaged for use. Figure 2 , Figure 3 shown.

[0089] 3. Mechanical properties of drug-loaded microneedles.

[0090] Use a push-pull force gauge and a digital scale to test the dexamethasone / sodium deoxycholate microneedle patch. Figure 4 shown.

[0091] 4. Detection of drug content uniformity in drug-loaded microneedles

[0092] Take 5 microneedle patches loaded with sodium deoxycholate from the same batch, put them into 1 mL of phosphate buffer (1×PBS, pH 7.4), shake them on a shaker for 2 hours to obtain a uniform solution and filter it with a 0.22 μm filter. The filtrate is measured by UV spectrophotometry to determine the uniformity of the sodium deoxycholate content in the microneedles. The standard curve is re-plotted with a 50-100 μg / mL standard solution to calculate the cumulative permeation amount, such as Figure 5 shown.

[0093] 5. In vitro transdermal diffusion experiment

[0094] The back skin of mice was depilated 12 hours before the experiment. At the beginning of the experiment, the mice were euthanized, and 3 pieces of full-thickness skin of the back were taken, about 1.5×1.5cm, and the subcutaneous fat was removed. After being cleaned with physiological saline, they were spread flat on tin foil. Dexamethasone / sodium deoxycholate microneedle patches (n=3) were applied to the outer surface of the mouse skin with the same force and time, and then placed between the receiving pool and the supply pool for transdermal diffusion. A magnetic stirrer was placed in each receiving pool, and PB solution was filled in each receiving pool to ensure that the solution infiltrated the peeling surface of the mouse skin and there were no bubbles between the solution and the skin. The receiving pool was placed in a preheated transdermal diffusion instrument, maintained at 33.5℃ water bath, with a speed of 350rpm / min, and timed. The whole process was protected from light. Samples were taken from the receiving pool at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24h, 100μL each time, and 100μL of release medium solution was immediately replenished. Finally, the obtained samples were measured by UV spectrophotometry to calculate the cumulative penetration, such as Figure 6 shown.

[0095] Experimental Example 2: Preparation of drug-loaded microneedles 2

[0096] 1. Preparation of Dexamethasone / PLGA Nanoparticles

[0097] 2 mg dexamethasone and 10 mg PLGA were dissolved in 1 mL acetone and added to an aqueous phase (2 mL) containing 0.5% (w / v) HS-15. The HS-15 was stirred at 300 rpm and room temperature (25°C ± 2°C) for 24 h to evaporate the organic solvent. After freeze drying, dexamethasone PLGA nanoparticle powder was obtained. Figure 1 .

[0098] 2. Preparation of Dexamethasone and Sodium Deoxycholate Microneedle Patches

[0099] Add 200 mg of sodium deoxycholate and 10 μL of 2-hydroxy-2-methylpropiophenone to 3 g of PEGDA, stir at 300 rpm and room temperature 25°C ± 2°C for 2 h in a dark environment, and mix thoroughly to obtain mold liquid 1. Take 200 μL of mold liquid 1 and add it to the cleaned and dried mold, evacuate at -0.1 MPa pressure for 30 min, centrifuge at 25°C, 3500 rpm for 20 min, and UV cure for 2 min. Then add 300 μL of mold liquid, centrifuge at 25°C, 3500 rpm for 10 min, and UV cure for 2 min. Microneedle array 1 is obtained.

[0100] Add a magnetic stirrer to the double distilled water and stir at 1000 rpm, and evacuate at -0.1 MPa pressure for 30 minutes. Weigh 240 mg HA and 3 mg of prepared dexamethasone PLGA nanoparticle powder and add them to 3 mL of double distilled water, stir at 300 rpm at room temperature for 7 hours to prepare mold liquid 2. Take 50 μL of mold liquid 2 and add it to the mold, evacuate at -0.1 MPa pressure for 30 minutes, centrifuge at 25°C, 3500 rpm, 15 minutes, and dry at 35°C for 2 hours. Add 150 μL of double distilled water, centrifuge at 25°C, 3500 rpm, 5 minutes, wet the surface of the needle body, reinsert the prepared microneedle array 1 into the mold, and dry at 35°C for 8 hours. The obtained microneedle patch is applied to medical tape and packaged for use. Figure 2 , Figure 3 shown.

[0101] 3. The microneedles were subjected to mechanical property testing, drug content uniformity testing, and in vitro transdermal diffusion experiments. The experimental steps were the same as those in Experimental Example 1.

[0102] Experimental Example 3: Preparation of drug-loaded microneedles 3

[0103] 1. Preparation of Dexamethasone / PLGA Nanoparticles

[0104] 2 mg dexamethasone and 2 mg PLGA were dissolved in 1 mL acetone and added to an aqueous phase (2 mL) containing 0.5% (w / v) HS-15. The HS-15 was stirred at 300 rpm and room temperature (25°C ± 2°C) for 24 h to evaporate the organic solvent. After freeze drying, dexamethasone PLGA nanoparticle powder was obtained. Figure 1 .

[0105] 2. Preparation of Dexamethasone and Sodium Deoxycholate Microneedle Patches

[0106] Add 160 mg of sodium deoxycholate and 15 μL of 2-hydroxy-2-methylpropiophenone to 1.28 g of PEGDA, stir at 300 rpm and room temperature 25°C ± 2°C for 2 h in a dark environment, and mix thoroughly. Take 200 μL of mold liquid and add it to the cleaned and dried mold, evacuate at -0.1 MPa pressure for 30 min, centrifuge at 25°C, 3500 rpm for 20 min, and UV cure for 2 min. Then add 300 μL of mold liquid, centrifuge at 25°C, 3500 rpm for 10 min, and UV cure for 2 min. Microneedle array 1 was obtained.

[0107] Add a magnetic stirrer to the double distilled water and stir at 1000rpm, and evacuate for 30min at -0.1MPa pressure. Weigh 60mgHA and 3mg of the prepared dexamethasone PLGA nanoparticle powder and add them to 3mL of double distilled water, stir at 300rpm at room temperature for 7h to prepare mold liquid 2, take 50μL of mold liquid 2 and add it to the mold, evacuate for 30min at -0.1MPa pressure, centrifuge at 25℃, 3500rpm, 15min, and dry at 35℃ for 2h. Add 150μL of double distilled water, centrifuge at 25℃, 3500rpm, 5min, wet the surface of the needle body, reinsert the prepared microneedle array 1 into the mold, and dry at 35℃ for 8h. The obtained microneedle patch is applied to medical tape and packaged for standby use.

[0108] 3. The microneedles were subjected to mechanical property testing, drug content uniformity testing, and in vitro transdermal diffusion experiments. The experimental steps were the same as those in Experimental Example 1.

[0109] Test Example 4: In vivo pharmacodynamics study

[0110] Preparation of mouse obesity model and changes in subcutaneous fat after drug administration

[0111] Mouse obesity model Specific method: Feed mice with 60% fat energy high-fat diet for 8 consecutive weeks to establish a stable mouse obesity model, and healthy mice fed with normal diet were used as controls.

[0112] Microneedle drug delivery and sampling methods Fig. 7A The efficacy of dexamethasone / sodium deoxycholate microneedles is shown in Table 1.

[0113] The experimental groups are set up as follows:

[0114] Comparative group 1: blank microneedle;

[0115] Comparative group 2: subcutaneous injection of sodium deoxycholate;

[0116] Comparative group 3: sodium deoxycholate microneedle treatment;

[0117] Experimental group 1: dexamethasone / sodium deoxycholate microneedle treatment group.

[0118] Table 1 Local fat reduction effect table (cycle is 14 days)

[0119]

[0120] in conclusion:

[0121] By administering the drug once, the therapeutic effect can be achieved while alleviating the unavoidable adverse reactions of the treatment and reducing the impact of the medication on the user's appearance.

[0122] The present invention administers drugs in the form of a double-layer soluble microneedle array, effectively combines anti-inflammatory drugs and fat-reducing drugs, and physically isolates them. The two drugs are not mixed together for use, thereby eliminating unknown effects on the body. The drugs can quickly achieve the effect of eliminating adverse reactions through the mass usage ratio of the two drugs and the mass usage ratio of the carrier. Hyaluronic acid, a fast-dissolving polymer material, is selected as the first layer of microneedle needle body, and nanoparticles prepared by slowly-releasing polylactic acid-glycolic acid copolymer (PLGA) and anti-inflammatory drugs are loaded. As the hyaluronic acid layer quickly dissolves in the body, the slowly-releasing anti-inflammatory drug nanoparticles remain in the body and are slowly released. At the same time, the second layer of the needle body layer containing the fat-reducing drug is exposed to release the drug. As the fat-reducing drug is released, fat cells are destroyed and an inflammatory response is generated. At this time, the slowly-releasing anti-inflammatory drug nanoparticles retained in the body continuously release the anti-inflammatory drug, reducing the inflammatory response, thereby alleviating the redness and swelling of the administration site.

[0123] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A double-layer soluble microneedle patch for local fat reduction, characterized in that: The microneedle comprises an anti-inflammatory drug and a fat-reducing drug, and the mass ratio of the anti-inflammatory drug to the fat-reducing drug is 1: (80-200); the needle body of the microneedle is divided into a first layer and a second layer from the outside to the inside, the first layer comprises an anti-inflammatory drug and a first carrier loaded with the anti-inflammatory drug, the anti-inflammatory drug and the first carrier are prepared into nanoparticles according to a mass ratio of 1: (1-5), the second layer comprises a fat-reducing drug and a second carrier loaded with the fat-reducing drug, the fat-reducing drug and the second carrier are according to a mass ratio of 1: (8-15), the first layer also comprises a soluble matrix, the soluble matrix is ​​sodium hyaluronate, the nanoparticles and the soluble matrix are according to a mass ratio of 1: (20~80), the first carrier and the second carrier are swellable materials, the first carrier is polylactic acid-glycolic acid copolymer (PLGA), and the second carrier is polyethylene glycol diacrylate (PEGDA); the first layer is loaded with a sustained-release anti-inflammatory drug; the needle body is one of a cone, a pyramid, and a bullet head shape, with a length of 650~850μm, a needle body bottom diameter of 300~400μm, and a tip diameter of less than 10μm; the fat-reducing drug is selected from at least one of a fat dissolving agent, a fat decomposing agent, and a fat metabolism promoter.

2. A method for preparing a double-layer soluble microneedle patch for local fat reduction according to claim 1, characterized in that: The anti-inflammatory drug and the fat-reducing drug are added into the microneedle mold containing holes in sequence according to the mass ratio of 1: (80-200); the steps are: 1) The fat-reducing drug and the second carrier are fully stirred at a mass ratio of 1: (8-15) to obtain a mold liquid 1, and the mold liquid 1 is added to a microneedle mold containing holes, so that the mold liquid fills the microholes and then solidifies to obtain a microneedle 1; 2) The anti-inflammatory drug and the first carrier are prepared into nanoparticles at a mass ratio of 1: (1-5), the nanoparticles and the soluble matrix are fully stirred at a mass ratio of 1: (20-80) to obtain a second mold liquid, the second mold liquid is added to a microneedle mold containing holes, the remaining mold liquid is dried and removed, the needle body is moistened with a volatile solvent, the microneedle one is inserted back into the mold and dried, and the double-layer microneedle is obtained after demolding.

3. Use of the double-layer soluble microneedle patch according to claim 1 in the preparation of a weight-loss drug for treating and eliminating redness and swelling.

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